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Polygenic Hypercholesterolaemia

​Background to Familial Hypercholesterolaemia genetic alterations

Familial Hypercholesterolaemia (FH) is a “monogenic” condition due to a single genetic alteration in one of 3 known FH causing genes, which results in very high levels of LDL- cholesterol in the blood. FH can lead to premature and recurrent cardiovascular disease (CVD) unless people are identified, diagnosed and treated with effective LDL- cholesterol lowering therapies.

The 3 genes responsible for FH are the LDL receptor gene (LDLR), the APOB gene and the PCSK9 gene. In the UK, the most common finding is an alteration in the LDLR gene, which is responsible for encoding the receptors for LDL-cholesterol removal from the blood. In the UK, over 200 different LDLR mutations have already been reported and it is thought to account for 93% of cases of FH identified. The APOB gene, which codes for apolipoprotein B (the major component of LDL-cholesterol that allows it to bind to the LDL receptor) is thought to occur in about 5% of cases. The PCSK9 gene, which codes for a protein involved in the breakdown of LDL receptors is thought to occur in only around 2% of cases.

NICE Guidance for FH

The National Institute for Health and Care Excellence (NICE) produced clinical guidelines for FH in 2008 which endorsed the Simon Broome Register criteria for the clinical diagnosis of FH and recommended that patients who met this criteria should be offered a genetic test to confirm their diagnosis to facilitate identification of FH in relatives by a process of genetic cascade testing.

A recent study by Professor Steve Humphries from UCL found that up to 60% of people with “clinically suspected FH” who underwent genetic testing were not found to have a genetic alteration in any of the 3 known FH causing genes, despite comprehensive DNA analysis. Professor Humphries explained some of the reasons for these findings, which could include the possible existence of 4th or 5th FH genes which were yet to be discovered, technical difficulties and most probably “over diagnosis” of the condition, where reported family history of raised cholesterol and early CVD was not sufficiently specific, giving false positives.

These findings led to more research for other FH causing genes. In addition to the three mentioned, using improved techniques including “next generation sequencing (NGS) and “genome wide association studies (GWAS). Using samples from an earlier healthy cohort study for comparison (the Whitehall II Study), Professor Humphries and colleagues studied the relationship between 12 common “small effect” LDL-cholesterol raising gene changes or SNPs, identified from GWAS, with LDL-cholesterol levels in the blood of clinically diagnosed FH patients with and without an FH causing mutation. From these results, the researchers proposed that people with a clinical diagnosis of FH, who did not have a major genetic alteration in any of the 3 known FH causing genes may have a raised LDL-cholesterol level due to the cumulative effect of several of these 12 changes or SNPs causing “polygenic hypercholesterolaemia”. This meant that their raised levels of LDL-cholesterol were not caused by the effect of a single major genetic alteration, but by the accumulation of the smaller effects exerted by a number of these more common LDL-cholesterol raising gene changes – polygenic meaning many genes. Each LDL cholesterol raising gene change would increase LDL cholesterol levels only slightly, but if an individual had several of these gene changes, then this could increase their LDL-cholesterol level to that high enough to meet the diagnostic criteria for FH.

The researchers also found that those individuals who did have an identified “monogenic” FH causing mutation frequently had a greater than average number of these small gene changes, giving them a high background of “polygenic” LDL-cholesterol. Families with identical LDLR genetic alterations were found to have marked differences in their LDL-cholesterol levels, survival and response to lipid lowering therapy, and this polygenic background was thought to contribute to these differences and variable levels reported in family members. In addition to this polygenic effect, a combination of environmental interactions such as lifestyle, diet, physical activity are also known to have an influence on LDL-cholesterol levels.

For example two sisters were tested for FH. The first sister had a total cholesterol level of 15mmol/L and the second sister had a total cholesterol level of 8.5mmol/L. The first sister was found to have a PCSK9 genetic alteration plus a polygenic background, whereas the second sister did not have the genetic alteration but did show the polygenic background. Both sisters met the diagnostic criteria for FH.

Recommendations from the researchers

The researchers recommend that a clinical diagnosis of FH should be restricted to those where a “monogenic” FH causing mutation is identified, and for those with no detected alteration, but with a high LDL genetic risk score based on the presence of several of the 12 LDL raising SNPs should be given the clinical diagnosis of “polygenic hypercholesterolaemia”. The researchers suggested that those with a polygenic diagnosis should not be prioritised for DNA cascade screening as cascade testing these families is unlikely to be cost effective.

CVD risk in those with a polygenic cause appears to be lower than those with a genetic alteration. However, if LDL cholesterol concentrations are raised then those with a polygenic diagnosis are still at risk of developing CVD and should be considered for LDL-cholesterol lowering therapy if they meet national treatment guidelines. All individuals with raised LDL-cholesterol qualify for statin treatment, whether or not their high cholesterol concentration has a mainly monogenic or polygenic cause.

Further investigation

For those who are found to have a low SNP score, this can indicate the presence of an undiagnosed monogenic cause. Specialists recognise there are at least 10% of those diagnosed as definite FH in which no monogenic mutation can be found and those with an additional low SNP score are eligible for the 100.000 Genome Project